Methods and compositions for the treatment of ophthalmic conditions

ABSTRACT

Compositions comprising at least two of a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), and an antibiotic find use in treating or preventing eye conditions in subjects in need thereof. Methods of treatment or prevention of eye conditions comprise administering an effective amount of the disclosed compositions to the affected eye(s). Methods of preparing a composition comprising an NSAID and antibiotic comprise separately complexing the NSAID and antibiotic with cyclodextrin.

PRIORITY

This application is a divisional of U.S. patent application Ser. No.16/118,484, filed Aug. 31, 2018, which claims priority to, and thebenefit of, U.S. Provisional Patent Application Ser. No. 62/553,584,filed Sep. 1, 2017, both which are hereby incorporated by reference intheir entirety.

BACKGROUND

Inflammatory reactions can cause tissue damage, promoting scarformation. In the eye and its appendages, this condition can lead toundesired functional impairments. For this reason, after cataract andother eye surgeries, medications such as anti-inflammatory drugs areoften administered to aid in the healing process. The anti-inflammatorydrugs are typically delivered to the ocular surface and the front of theeye in the form of eye drops.

The separate application of two or more different active ingredients isnot ideal for both compliance and pharmacokinetic reasons. Many patientsundergoing ocular surgery, particularly cataract surgery, are of anadvanced age with impaired vision, making it difficult to handle theadministration of multiple formulations. Further, contact time andabsorption of the applied active ingredients are difficult to calculatedue to their reciprocal displacement from the tear film. In order toavoid mistakes when administering multiple preparations, the patientmust strictly adhere to application intervals. In contrast, if acombination product is used, i.e., a product comprising at least twoactive agents, each of the active ingredients are applied to theconjunctival sac in a defined proportion, so that reciprocaldisplacement can be ruled out.

Therefore, there is a need in the art for a combination product thatcomprises at least two therapeutically active agents useful for treatingor preventing ophthalmic conditions and is characterized by improvedcompliance, improved efficacy, and reduction of side effects associatedwith topical administration of medications.

BRIEF SUMMARY

Disclosed herein are ophthalmic compositions comprising at least two ofthe following therapeutically active agents: a corticosteroid, anon-steroidal anti-inflammatory drug (NSAID), and an antibiotic. Suchcompositions find use in treating or preventing ophthalmic conditions,such as ocular inflammation or ocular infection that can occur after eyesurgery. In one embodiment, the ophthalmic composition is in the form ofliquid drops, a gel, or an ointment, and a therapeutically effectiveamount of the ophthalmic composition is applied topically to at leastone affected eye of a subject having an ophthalmic condition or at riskfor developing an ophthalmic condition in order to treat or prevent thecondition.

According to aspects of the invention illustrated herein, there isprovided a composition comprising a non-steroidal anti-inflammatory drug(NSAID) and a corticosteroid. In accordance with aspects of the presentinvention, the composition may further include an antibiotic. Inaccordance with yet further aspects of the present invention, thecomposition may further include a complexing agent. In accordance withyet further aspects of the present invention, the composition mayfurther include a viscosifying agent.

According to aspects of the invention illustrated herein, there isprovided a composition comprising a corticosteroid, a non-steroidalanti-inflammatory drug (NSAID), an antibiotic, and optionally aviscosifying agent, wherein the composition is formulated as an eye gel.

According to aspects of the invention illustrated herein, there isprovided a method of treating and/or preventing an ophthalmic conditionin a subject, the method comprising topically administering an effectiveamount of the composition to an eye of a subject in need thereof.

According to aspects of the invention illustrated herein, there isprovided a method for preparing a composition comprising prednisolone,diclofenac, and ofloxacin in a gel formulation, the method can include:producing a methylcellulose gel to form Solution 1; complexing ofloxacinwith gamma-cyclodextrin to form Solution 2; complexing diclofenac withgamma-cyclodextrin to form Solution 3; combining Solutions 2 and 3 toform Solution 4; adding mannitol to Solution 4 to form Solution 5;Solutions 1 and 5 to form Solution 6; and adding prednisolone acetate toSolution 6, thereby forming the composition, wherein steps a)-c) can beperformed in any order, and wherein step a) can be performed before,simultaneously, or after any one of steps b)-f).

Methods for preparing the ophthalmic compositions are also providedherein and comprise separately complexing the NSAID and the antibioticwith cyclodextrin.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter withreference to the accompanying experiments and/or drawings, in whichsome, but not all embodiments of the inventions are shown. It is to beunderstood that the following detailed description is provided to givethe reader a fuller understanding of certain embodiments, features, anddetails of aspects of the invention, and should not be interpreted as alimitation of the scope of the invention. Indeed, many differentembodiments are described below and the description provided belowshould not be construed as limited to only these embodiments; rather,these embodiments are provided so that this disclosure will satisfyapplicable legal requirements. Like numbers refer to like elementsthroughout.

I. Definitions

In order for the present disclosure to be more readily understood,certain terms are first defined below. Additional definitions for thefollowing terms and other terms may be set forth through thespecification. If a definition of a term set forth below is inconsistentwith a definition in an application or patent that is incorporated byreference, the definition set forth in this application should be usedto understand the meaning of the term.

As used in this specification and the appended claims, the singularforms “a,” “an,” and “the” include plural references unless the contextclearly dictates otherwise. Thus, for example, a reference to “a method”includes one or more methods, and/or steps of the type described hereinand/or which will become apparent to those persons skilled in the artupon reading this disclosure and so forth.

As used throughout, ranges are used as shorthand for describing each andevery value that is within the range. Any value within the range can beselected as the terminus of the range. In addition, all references citedherein are hereby incorporated by reference in their entireties. In theevent of a conflict in a definition in the present disclosure and thatof a cited reference, the present disclosure controls

Unless otherwise specified, all percentages and amounts expressed hereinand elsewhere in the specification should be understood to refer topercentages by weight. The amounts given are based on the active weightof the material.

As used herein, the term “about” or “approximately” refers to avariation of 10% from the indicated values (e.g., 1.0%, 1.5%, 2.0%,etc.), or in case of a range of values, means a 10% variation from boththe lower and upper limits of such ranges unless otherwise stated orotherwise evident from the context (except where such a number wouldexceed a possible value).

The term “eye condition” or “ophthalmic condition” refers to any of awide variety of pathological ocular conditions or physiologicabnormalities of the eye, such as glaucoma, ocular inflammatoryconditions such as keratitis, uveitis, allergy, and dry eye syndrome,ocular infections, ocular allergies, cancerous growth, neo vessel growthoriginating from the cornea, retinal edema, macular edema, diabeticretinopathy, retinopathy of prematurity, degenerative diseases of theretina (macular degeneration, retinal dystrophies), retinal diseasesassociated with glial proliferation, and the like. Non-limitingophthalmic conditions that are treated with the presently disclosedcompositions and methods include, but are not limited to, age relatedmacular degeneration, alkaline erosive keratoconjunctivitis, allergicconjunctivitis, allergic keratitis, anterior uveitis, Behcet's disease,blepharitis, blood-aqueous barrier disruption, chorioiditis, chronicuveitis, conjunctivitis, contact lens-induced keratoconjunctivitis,corneal abrasion, corneal trauma, corneal ulcer, crystallineretinopathy, cystoid macular edema, dacryocystitis, diabetickeratopathy, diabetic macular edema, diabetic retinopathy, dry eyedisease, dry age-related macular degeneration, eosinophilic granuloma,episcleritis, exudative macular edema, giant cell arteritis, giantpapillary conjunctivitis, glaucoma, glaucoma surgery failure, graftrejection, herpes zoster, inflammation after cataract surgery,iridocorneal endothelial syndrome, iritis, keratoconjunctiva sicca,keratoconjunctival inflammatory disease, keratoconus, necrotickeratitis, neovascular diseases involving the retina, uveal tract orcornea such as neovascular glaucoma, corneal neovascularization,neovascularization following a combined vitrectomy and lensectomy,neovascularization of the optic nerve, and neovascularization due topenetration of the eye or contusive ocular injury, neuroparalytickeratitis, non-infectious uveitisocular herpes, ocular lymphoma, ocularrosacea, ophthalmic infections, ophthalmic pemphigoid, optic neuritis,panuveitis, papillitis, pars planitis, persistent macular edema,phacoanaphylaxis, posterior uveitis, post-operative inflammation,proliferative diabetic retinopathy, proliferative sickle cellretinopathy, proliferative vitreoretinopathy, retinal artery occlusion,retinal detachment, retinal vein occlusion, retinitis pigmentosa,retinopathy of prematurity, rubeosis iritis, scleritis, Stevens-Johnsonsyndrome, sympathetic ophthalmia, temporal arteritis, thyroid associatedophthalmopathy, uveitis, vernal conjunctivitis, vitamin Ainsufficiency-induced keratomalacia, vitreitis, and wet age-relatedmacular degeneration.

“Efficacy” means the ability of an active agent administered to apatient or subject to produce a therapeutic effect in the patient.

“Side effect” is defined herein as a secondary and usually adverseeffect of a drug.

Terms such as “treating” or “treatment” or “to treat” or “alleviating”or “to alleviate” refer to therapeutic measures that cure, slow down,lessen symptoms of, reverse, and/or halt progression of a diagnosedpathologic condition or disorder. Thus, those in need of treatmentinclude those already with the disorder. Beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease, stabilized (i.e., not worsening)state of disease, delay or slowing of disease progression, ameliorationor palliation of the disease state, and remission (whether partial ortotal), whether detectable or undetectable. “Treatment” can also meanprolonging survival as compared to expected survival if not receivingtreatment.

As used herein “preventing” refers to the administration of atherapeutically effective amount of the compositions described herein toa subject to protect the subject from developing inflammation and/or apathological condition or disorder of the eye. Thus, the term“preventing” when used in the context of a disease or disease conditionmeans prophylactic administration of the described compositions to stopor otherwise delay the onset of a pathological hallmark or symptom ofthe ocular disease or disorder.

A “pharmaceutical composition” is defined herein as comprising at leastone therapeutic agent, otherwise known as active pharmaceutical agent(API), e.g., corticosteroid, NSAID, antibiotic, and at least onepharmaceutically acceptable carrier.

An “ophthalmic composition” or “ophthalmic preparation” or “ophthalmicformulation” or the like is defined herein as a pharmaceuticalcomposition formulated for ocular administration.

“Pharmaceutically acceptable” means that which is generally safe,non-toxic and neither biologically nor otherwise undesirable andincludes that which is acceptable for veterinary use as well as humanpharmaceutical use.

The term “pharmaceutically acceptable carrier” refers to a carriermedium which does not interfere with the effectiveness of the biologicalactivity of the active ingredient(s) and which is not excessively toxicto the host at a concentration at which it is administered. The termincludes solvents, dispersion media, antibacterial and antifungalagents, isotonic agents, adsorption delaying agents, and the like. Theuse of such media and agents for pharmaceutically active substances iswell known in the art (see, for example, “Remington's PharmaceuticalSciences”, E. W. Martin, 18^(th)Ed., 1990, Mack Publishing Co.: Easton,Pa., which is incorporated herein by reference in its entirety).

The terms “therapeutic agent”, “drug”, “pharmaceutically activesubstance”, “active pharmaceutical ingredient” are used hereininterchangeably. They refer to a substance, molecule, compound, agent,factor or composition effective in the treatment or prevention of adisease or condition.

As used herein, the term “effective amount”, refers to any amount of acompound, agent or composition that is sufficient to fulfill itsintended purpose(s), e.g., a desired biological or medicinal response ina tissue, system or subject. For example, in certain embodiments of thepresent invention, the purpose(s) may be: to slow down or stop theprogression, aggravation, or deterioration of the symptoms of an eyecondition, to bring about amelioration of the symptoms of the condition,and/or to cure the condition. Determination of an effective amount iswell within the ordinary skill in the art of pharmaceutical sciences andmedicine, in that it may depend on various biological factors orindividual variations and response to treatments.

By “therapeutically effective dose or amount” is intended an amount ofthe ophthalmic composition that when administered brings about apositive therapeutic response with respect to treatment of a patientwith an ophthalmic condition, e.g., an improvement in the condition canbe evidenced by, for example, a delayed onset of clinical symptoms ofthe condition, a reduction in severity of some or all clinical symptomsof the condition, a slower progression of the condition, an improvementin the overall health or well-being of the subject, or by otherparameters well known in the art that are specific to the particularcondition.

By “prophylactically effective dose or amount” or is intended an amountof the ophthalmic composition that when administered to a patient atrisk of developing an ophthalmic condition is able to prevent or slowthe development of the condition.

The term “corticosteroid”, as used herein, refers to any of a widevariety of drugs that are analogues of cortisol, a hormone which isnaturally produced in the adrenal cortex, and function as ananti-inflammatory. Examples of corticosteroids include, but are notlimited to, betamethasone, budenoside, cortisone, dexamethasone,hydrocortisone, methylprednisoline, prednisolone, prednisone, andtriamcinolone. In certain preferred embodiments of the presentinvention, corticosteroids are effective in the treatment or preventionof an eye disease or condition via topical administration.

The term “non-steroidal anti-inflammatory drug” or “NSAID,” as usedherein, refers to a class of therapeutic agents with anti-inflammatoryactions that are distinguished from the cyclic organic steroid compoundscharacterized by a four-ring steroidal structure. Examples of NSAIDsinclude, but are not limited to, diclofenac, ketorolac tromethamine,bromfenac, nepafenac, derivatives thereof, and salts thereof.

The terms “antibiotic,” and “antibacterial” used interchangeably herein,refer to compounds that either kill (bactericidal) or inhibit the growth(bacteriostatic) of at least one species of bacteria.

The term “viscosifying agent” or “viscosifier,” as used herein, refersto compounds that increase the viscosity of a liquid when added thereto.

As used herein, the term “physiologically tolerable salt” refers to anyacid addition or base addition salt that retains the biological activityand properties of the corresponding free base or free acid,respectively, and that is not biologically or otherwise undesirable.Acid addition salts are formed with inorganic acids (e.g., hydrochloric,hydrobromic, sulfuric, nitric, phosphoric acids, and the like); andorganic acids (e.g., acetic, propionic, pyruvic, maleic, malonic,succinic, fumaric, tartaric, citric, benzoic, mandelic, methanesulfonic,ethanesulfonic, p-toluenesulfonic, salicylic acids, and the like. Baseaddition salts can be formed with inorganic bases (e.g., sodium,potassium, lithium, ammonium, calcium, magnesium, zinc, aluminium salts,and the like), and organic bases (e.g., salts of primary, secondary andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-dimethyl-aminoethanol,2-diethylaminoethanol, trimethamine, dicyclohexyl-amine, lysine,arginine, histidine, caffeine, procaine, hydrabanine, choline, betaine,ethylene-diamine, glycosamine, methylglucamine, theobromine, purines,piperazine, N-ethylpiperidine, polyamine resins, and the like).

As used herein, the term “derivative” in the context of a chemicalcompound refers to a chemical analogue that resembles the chemicalcompound in structure and substantially retains the activity of thechemical compound.

The term “topical formulation” and “topical composition” are used hereininterchangeably. They refer to a composition formulated such that theactive ingredient(s) of the composition may be applied for directadministration to the surface of the eye and from which an effectiveamount of the active ingredient(s) is released. Examples of topicalformulations include, but are not limited to, lotions, sprays,ointments, creams, gels, pastes, and the like.

The term “topical”, when used herein to characterize the delivery,administration or application of a composition of the present invention,is meant to specify that the composition is delivered, administered orapplied directly to the site of interest (i.e., to the eye) for alocalized effect. Preferably, topical administration is effected withoutany significant absorption of components of the composition into thesubject's blood stream (to avoid a systemic effect). In certainpreferred embodiments of the present invention, topical administrationof a composition is effected without any significant absorption ofcomponents of the composition into the subject's eye tissues, such asthe aqueous humor, and corneal and conjunctival tissues.

The term “non-invasive”, when used herein refers to a method or mode ofadministration that does not rupture or puncture (e.g., by a mechanicalmeans) a biological membrane to which a therapeutic agent is beingdelivered.

The term “ophthalmic”, as used herein in connection with a composition,refers to a composition intended to be administered to the eye and whichpresents a pharmaceutical effect.

By “subject” or “individual” or “animal” or “patient” or “mammal,” ismeant any subject, particularly a mammalian subject, for whom diagnosis,prognosis, or therapy is desired. Mammalian subjects include humans,domestic animals, farm animals, and zoo, sports, or pet animals such asdogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows,bears, and so on. The meaning of the terms “eukaryote”, “animal”,“mammal”, etc. is well known in the art and can, for example, be deducedfrom Wehner and Gehring (1995; Thieme Verlag). In the context of thisinvention, it is also envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Non-limiting examples of agronomically important animals aresheep, cattle and pigs, while, for example, cats and dogs may beconsidered as economically important animals. In one embodiment, thesubject/patient is a mammal; in another embodiment, the subject/patientis a human or a non-human mammal (such as, e.g., a guinea pig, ahamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, anape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, agibbon, a sheep, cattle, or a pig); in a further embodiment thesubject/patient is a human. In many embodiments, the subject is a humanbeing. The terms “individual” and “subject” do not denote a particularage, and thus encompass adults, children, and newborns.

II. Ophthalmic Compositions

Disclosed herein are ophthalmic compositions for administration to theeye for the treatment or prevention of eye conditions. The presentlydisclosed ophthalmic compositions eliminate the undesirable side effectsthat are generally associated with therapeutic ocular compositions.

The presently disclosed compositions comprise at least two of acorticosteroid, a non-steroidal anti-inflammatory drug (NSAID), and anantibiotic.

In one embodiment, the composition includes a corticosteroid, anon-steroidal anti-inflamatory medication (NSAID), and an antibiotic.

In other embodiments, the composition comprises a corticosteroid and anantibiotic.

In yet other embodiments, the composition comprises a corticosteroid andan NSAID.

In still other embodiments, the composition comprises an NSAID and anantibiotic.

Corticosteroids are the most frequently prescribed class of therapeuticsin ophthalmology. In particular, topical corticosteroids haverevolutionized the practice of ophthalmology and ophthalmic care when itcomes to preventing or treating ocular inflammation due to trauma,chemicals, infections, allergies or other causes. Corticosteroids aresynthetic drugs that mimic steroid hormones naturally produced by thebody. These steroid hormones have a wide variety of actions and controlfunctions that are involved in a number of important physiologicalsystems including stress responses, immune responses, inflammatoryresponses, carbohydrate metabolism, protein catabolism and bloodelectrolyte levels. In addition to regulating inflammation,corticosteroids also have the ability to affect these otherphysiological systems, resulting in many potential risks and sideeffects. Corticosteroids useful in the presently disclosed compositionsand methods include, but are not limited to, prednisolone,difluprednate, loteprednol etabonate, fluorometholone, dexamethasone,rimexolone, medrysone, triamcinolone acetonide, and pharmaceuticallyacceptable equivalents and derivatives thereof.

For topical treatment, corticosteroids, such as prednisolone have provento be particularly useful due to their marked antiphlogistic andantiproliferative properties. Prednisolone, in particular, has anespecially potent anti-inflammatory effect and a favorable safetyprofile. Thus, in particular embodiments, the presently disclosedcompositions and methods comprise prednisolone and/or a salt orderivative thereof, such as prednisolone acetate, prednisolone pivalate,or prednisolone phosphate. In some of these embodiments, theprednisolone salt is prednisolone acetate.

In certain embodiments, the concentration (weight/volume) ofcorticosteroids (e.g., prednisolone, dexamethasone) in the presentlydisclosed compositions is between 0.05 and 2%, including, but notlimited to, 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v), 0.09%(w/v), 0.1% (w/v), 0.2% (w/v), 0.3% (w/v), 0.4% (w/v), 0.5% (w/v), 0.6%(w/v), 0.7% (w/v), 0.8% (w/v), 0.9% (w/v), 1% (w/v), 1.1% (w/v), 1.2%(w/v), 1.3% (w/v), 1.4% (w/v), 1.5% (w/v), 1.6% (w/v), 1.7% (w/v), 1.8%(w/v), 1.9% (w/v), and 2% (w/v). In some of these embodiments, thepresently disclosed compositions comprise corticosteroids (e.g.,prednisolone) at a concentration between 0.25% (w/v) and 1% (w/v). Inparticular embodiments, the concentration of the corticosteroid (e.g.,prednisolone) within the presently disclosed compositions is about 0.5%(w/v).

In another embodiment, the corticosteroids is included in an amount ofabout 0.05% (w/v) to about 1.75% (w/v), or from 0.10% (w/v) to 1.50%(w/v), or 0.15% (w/v) to 1.25% (w/v), or 0.20% (w/v) to 0.100% (w/v), or0.25% (w/v) to 0.75% (w/v), or 0.30% (w/v) to 0.50% (w/v), or 0.35%(w/v) to 0.45% (w/v), or from 0.40% (w/v) to 0.45% (w/v).

In a further embodiment, the corticosteroids is included in an amount ofabout 0.05% (w/v)±0.05 (w/v), 0.10% (w/v)±0.05 (w/v), 0.20% (w/v)±0.10(w/v), 0.30% (w/v)±0.25 (w/v), 0.40% (w/v)±0.25 (w/v), or about 0.50%(w/v)±0.25 (w/v), or about 0.60% (w/v)±0.50 (w/v), or about 0.70%(w/v)±0.50 (w/v), or about 0.80% (w/v)±0.75 (w/v), or about 0.90%(w/v)±0.75 (w/v), or about 1.0% (w/v)±1.0 (w/v), or about 1.1% (w/v)±1.0(w/v), or about 1.2% (w/v)±1.0 (w/v), or about 1.3% (w/v)±1.25 (w/v), orabout 1.4% (w/v)±1.25 (w/v), or about 1.50% (w/v)±1.50 (w/v), or about1.6% (w/v)±1.5 (w/v), or about 1.7% (w/v)±1.5 (w/v), or about 1.8%(w/v)±1.75 (w/v), or from about 1.9% (w/v)±1.75 (w/v).

In an alternative embodiment, the corticosteroids is included in anamount of about 0.05% (w/v) to about 0.10% (w/v), or from 0.10% (w/v) to0.20% (w/v), or 0.20% (w/v) to 0.30% (w/v), or 0.30% (w/v) to 0.40%(w/v), or 0.40% (w/v) to 0.50% (w/v), or 0.50% (w/v) to 0.60% (w/v), or0.60% (w/v) to 0.70% (w/v), or 0.70% (w/v) to 0.80% (w/v), or 0.80%(w/v) to 0.90% (w/v), or 0.90% (w/v) to 1.0% (w/v), or 1.1% (w/v) to1.2% (w/v), or 1.2% (w/v) to 1.3% (w/v), or 1.3% (w/v) to 1.4% (w/v), or1.4% (w/v) to 1.5% (w/v), or 1.5% (w/v) to 1.6% (w/v), or 1.6% (w/v) to1.7% (w/v), or 1.7% (w/v) to 1.8% (w/v), or 1.8% (w/v) to 1.9% (w/v), or1.9% (w/v) to 2.0% (w/v). In another embodiment, the corticosteroids isincluded in an amount of about 0.05% (w/v) to about 0.15% (w/v), or from0.15% (w/v) to 0.25% (w/v), or 0.25% (w/v) to 0.35% (w/v), or 0.35%(w/v) to 0.45%, 0.45% (w/v) to 0.55% (w/v), or 0.55% (w/v) to 0.65%(w/v), or 0.65% (w/v) to 0.75% (w/v), or 0.75% (w/v) to 0.85% (w/v), or0.85% (w/v) to 0.95% (w/v), or 0.95% (w/v) to 1.05% (w/v), or 1.05%(w/v) to 1.15% (w/v), or 1.15% (w/v) to 1.25% (w/v), or 1.25% (w/v) to1.35% (w/v), or 1.35% (w/v) to 1.45% (w/v), or 1.45% (w/v) to 1.55%(w/v), or 1.55% (w/v) to 1.65% (w/v), or 1.65% (w/v) to 1.75% (w/v), or1.75% (w/v) to 1.85% (w/v), or from 1.85% (w/v) to 1.95% (w/v).

A second class of anti-inflammatory drugs, namely non-steroidalanti-inflammatory drugs (NSAIDs) such as diclofenac, can also be foundin the presently disclosed compositions and methods. An additionalbenefit of NSAIDs, besides their anti-inflammatory action, is theiranalgesic properties. Moreover, NSAIDs inhibit miosis (pupilconstriction) which is useful in the setting of ocular surgery. Thirdly,NSAIDs are used after ocular surgery for the prevention and treatment ofcystoid macular edema (CME, retinal swelling), a common and known sideeffect after cataract surgery that affects 4-21% of patients.Non-limiting examples of NSAIDs useful in the presently disclosedcompositions and methods include ketorolac tromethamine, bromfenac,diclofenac, nepafenac, pharmaceutically acceptable equivalents andderivatives thereof. In particular embodiments, the presently disclosedcompositions and methods comprise diclofenac.

In certain embodiments, the concentration (weight/volume) of NSAIDs(e.g., diclofenac, bromfenac) in the presently disclosed compositions isbetween 0.05% and 0.5% (w/v) (weight/volume), including, but not limitedto, 0.05% (w/v), 0.06% (w/v), 0.07% (w/v), 0.08% (w/v), 0.09% (w/v),0.1% (w/v), 0.11% (w/v), 0.12% (w/v), 0.13% (w/v), 0.14% (w/v), 0.15%(w/v), 0.16% (w/v), 0.17% (w/v), 0.18% (w/v), 0.19% (w/v), 0.2% (w/v),0.21% (w/v), 0.22% (w/v), 0.23% (w/v), 0.24% (w/v), 0.25% (w/v), 0.26%(w/v), 0.27% (w/v), 0.28% (w/v), 0.29% (w/v), 0.3% (w/v), 0.31% (w/v),0.32% (w/v), 0.33% (w/v), 0.34% (w/v), 0.35% (w/v), 0.36% (w/v), 0.37%(w/v), 0.38% (w/v), 0.39% (w/v), 0.4% (w/v), 0.41% (w/v), 0.42% (w/v),0.43% (w/v), 0.44% (w/v), 0.45% (w/v), 0.46% (w/v), 0.47% (w/v), 0.48%(w/v), 0.49% (w/v), and 0.5% (w/v). In some of these embodiments, thepresently disclosed compositions comprise NSAIDs (e.g., diclofenac) at aconcentration between 0.05% and 0.2% (w/v). In particular embodiments,the concentration of the NSAID (e.g., diclofenac) within the presentlydisclosed compositions is about 0.1% (w/v).

In another embodiment, the NSAID is included in an amount of about 0.05%(w/v) to about 0.50% (w/v), or from 0.10% (w/v) to 0.45% (w/v), or 0.15%(w/v) to 0.40% (w/v), or 0.20% (w/v) to 0.35% (w/v), or from 0.25% (w/v)to 0.30% (w/v).

In a further embodiment, the NSAID is included in an amount of about0.05% (w/v)±0.05 (w/v), 0.10% (w/v)±0.5 (w/v), 0.20% (w/v)±0.75 (w/v),0.30% (w/v)±0.75 (w/v), 0.40% (w/v)±0.75 (w/v), or from about 0.50(w/v)±0.25 (w/v).

In an alternative embodiment, the NSAID is included in an amount ofabout 0.05% (w/v) to about 0.10% (w/v), or from 0.10% (w/v) to 0.15%(w/v), or 0.15% (w/v) to 0.20% (w/v), or 0.25% (w/v) to 0.30% (w/v), or0.30% (w/v) to 0.35% (w/v), or 0.35% (w/v) to 0.40% (w/v), or 0.40%(w/v) to 0.45% (w/v), or from 0.45% (w/v) to 0.50% (w/v). In anotherembodiment, the NSAID is included in an amount of about 0.05% (w/v) toabout 0.15% (w/v), or from 0.15% (w/v) to 0.25% (w/v), or 0.25% (w/v) to0.35% (w/v), or from 0.35% (w/v) to 0.45%.

Until now, no combination drugs comprising both corticosteroids andNSAIDs exist in the market. Furthermore, combining two different classesof anti-inflammatory drugs such as diclofenac and prednisolone for thetreatment of eye conditions, such as post-operative inflammationprovides several benefits. First, such a composition combines the potentanti-inflammatory action of a corticosteroid with those of an NSAID,resulting in an additive, synergistic anti-inflammatory, and/orunexpectedly beneficial medical effect in terms of preventing and/ortreating the eye conditions and diseases discussed herein. Additionally,NSAIDs are approved for post-operative pain management of cataractsurgery, the maintenance of mydriasis during surgery, and for theprevention and treatment of CME. Moreover, unlike diclofenac, which isapproved for post-operative management, prednisolone, is indicated forthe treatment of many kinds of ocular inflammation such asconjunctivitis, keratitis, and uveitis. Clinical data show thattreatment using a combination of a corticosteroid such as prednisoloneand an NSAID such as ketorolac displays superior clinical efficacy intreating and/or preventing CME than monotherapy with prednisolone orNSAID alone (Heier et al., American Academy of Ophthalmology, Vol. 107,No. 11, 2000).

In the case of inflammation that occurs concomitantly with a bacterialinfection or the risk of bacterial infection, the presently disclosedcompositions and methods comprise a combination of anti-inflammatorydrugs with an appropriate antibiotic.

A typical scenario in which the combined treatment withanti-inflammatory drugs and antibiotics is indicated is ocular surgery.The surgical intervention typically induces an inflammatory response anddue to the incision, the danger of infection is high.

In some embodiments, the presently disclosed compositions comprise abroad spectrum antibiotic. As used herein, the term “broad spectrumantibiotic” refers to an antibiotic that is effective against a widerange of bacterial species spanning different bacterial families. Insome embodiments, the broad spectrum antibiotic is effective againstspecies that are either Gram-negative or Gram-positive bacteria.

In some embodiments, the antibiotic is a gyrase inhibitor, such asofloxacin. The presently disclosed compositions and methods can comprisean antibiotic within the class of quinolones, such as fluoroquinolones.Quinolones are broad-spectrum antibiotics that prevent bacterial DNAfrom unwinding and duplicating and have the following core structure,wherein the fluorine (F) substituent may or may not be present (FormulaI):

In some embodiments, the antibiotic is a fluoroquinolone, which is aquinolone having a fluorine atom attached to the central ring system.

Non-limiting examples of antibiotics useful in the presently disclosedcompositions and methods include, but are not limited to, gatifloxacin,moxifloxacin, ciprofloxacin, ofloxacin, levofloxacin, besifloxacin,fluoroquinolone, pharmaceutically acceptable equivalents and derivativesthereof. Other antibiotics may include, but are not limited to,penicillins, aminoglycosides, macrolides, monobactams, rifamycins,tetracyclines, chloramphenicol, clindamycin, lincomycin, imipenem,fusidic acid, novobiocin, fosfomycin, fusidate sodium, neomycin,polymyxin, capreomycin, colistimethate, colistin, gramicidin,minocycline, doxycycline, vanomycin, bacitracin, kanamycin, gentamycin,erythromycin, and cephalosporins. In certain embodiments, thecompositions and methods comprise ofloxacin because of its wide spectrumof action and its ability to efficiently penetrate tissues.

In certain embodiments, the concentration (weight/volume) of antibiotics(e.g., ofloxacin) in the presently disclosed compositions is between0.1% (w/v) and 1% (w/v), including, but not limited to, 0.1% (w/v), 0.2%(w/v), 0.3% (w/v), 0.4% (w/v), 0.5% (w/v), 0.6% (w/v), 0.7% (w/v), 0.8%(w/v), 0.9% (w/v), and 1% (w/v). In some of these embodiments, thepresently disclosed compositions comprise antibiotics (e.g., ofloxacin)at a concentration between 0.2% (w/v) and 0.5% (w/v). In particularembodiments, the concentration of the antibiotic (e.g., ofloxacin)within the presently disclosed compositions is about 0.3% (w/v).

In another embodiment, the antibiotic is included in an amount of about0.10% (w/v) to about 0.90% (w/v), or from 0.20% (w/v) to 0.80% (w/v), or0.30% (w/v) to 0.70% (w/v), or 0.40% (w/v) to 0.60% (w/v), or from 0.45%(w/v) to 0.55% (w/v).

In a further embodiment, the antibiotic is included in an amount ofabout 0.10% (w/v)±0.05 (w/v), 0.20% (w/v)±0.10 (w/v), 0.30% (w/v)±0.25(w/v), 0.40% (w/v)±0.25 (w/v), 0.50% (w/v)±0.45 (w/v), or about 0.60(w/v)±0.50 (w/v), or about 0.70 (w/v)±0.50 (w/v), or about 0.80(w/v)±0.75 (w/v), or about 0.90 (w/v)±0.75 (w/v), or from about 0.90(w/v)±0.75 (w/v).

In an alternative embodiment, the antibiotic is included in an amount ofabout 0.10% (w/v) to about 0.15% (w/v), or from 0.15% (w/v) to 0.20%(w/v), or 0.20% (w/v) to 0.25% (w/v), or 0.25% (w/v) to 0.30% (w/v), or0.30% (w/v) to 0.35% (w/v), or 0.35% (w/v) to 0.40% (w/v), or 0.40%(w/v) to 0.45% (w/v), or 0.45% (w/v) to 0.50% (w/v), or 0.50% (w/v) to0.55% (w/v), or 0.55% (w/v) to 0.60% (w/v), or 0.60% (w/v) to 0.65%(w/v), or 0.65% (w/v) to 0.70% (w/v), or 0.70% (w/v) to 0.75% (w/v), or0.75% (w/v) to 0.80% (w/v), or 0.80% (w/v) to 0.85% (w/v), or 0.85%(w/v) to 0.90% (w/v), or 0.90% (w/v) to 0.95% (w/v), or from 0.95% (w/v)to 1.0% (w/v). In another embodiment, the antibiotic is included in anamount of about 0.10% (w/v) to about 0.20% (w/v), or from 0.20% (w/v) to0.30% (w/v), or 0.30% (w/v) to 0.40% (w/v), or 0.40% (w/v) to 0.50%(w/v), or 0.50% (w/v) to 0.60% (w/v), or 0.60% (w/v) to 0.70% (w/v), or0.70% (w/v) to 0.80% (w/v), or 0.80% (w/v) to 0.90% (w/v), or from 0.90%(w/v) to 1.00% (w/v).

Likewise, until now, no combination drugs comprising both an antibioticand an NSAID exist in the market. Such a combination compositionprovides the potent antibiotic action of a broad spectrum antibioticwith the aid of an NSAID, resulting in an additive, synergisticantibiotic, and/or unexpectedly beneficial medical effect in terms ofpreventing and/or treating the eye conditions and diseases discussedherein. For instance, in one reported study, CME patients were enrolledin a study to examine the benefits of daily ocular dropwise addition ofan antibiotic and an NSAID. In this study, the postoperative regimen ofCME patients included administration of both TobraDex®(tobramycin-dexamethasone, an antibiotic) and Acular® (ketorolactromethamine, an NSAID) drops, 4 times per day, to a total of 5 cc and10 cc, respectively, in each eye. Remarkably, this study found no casesof postoperative CME or iritis in 540 consecutive eyes after thistreatment regimen (Arshinoff et al, J Cataract Refract Surg, Vol. 29,July 2003). These drops were administered separately and not as oneformulation. Had this medication been delivered as a simple,easy-to-use, efficient, and synergistic formulation comprising both theNSAID and the antibiotic in one application, even more profound outcomeslikely would have been observed. Thus, in some embodiments, thecompositions described herein include an NSAID (e.g., diclofenac) and anantibiotic (e.g., ofloxacin). In yet another embodiment, the compositionincludes a corticosteroid (e.g., prednisolone) and an antibiotic (e.g.,ofloxacin). In certain embodiments, the composition comprises acorticosteroid (e.g., prednisolone) and an NSAID (e.g., diclofenac). Incertain embodiments, the composition comprises a corticosteroid (e.g.,prednisolone), an NSAID (e.g., diclofenac), and an antibiotic (e.g.,ofloxacin).

The ophthalmic composition disclosed herein, in one embodiment, are usedfor the prevention and/or treatment of eye conditions. Thus,pharmaceutical compositions for the treatment or prevention of eyediseases or conditions in a subject are also provided herein comprisingthe presently disclosed compositions and a pharmaceutically acceptablecarrier.

In some embodiments, the presently disclosed compositions comprise acomplexing agent. In an embodiment, the complexing agent has ahydrophobic core and a hydrophilic exterior. An example of a complexingagent is β-cyclodextrin, which may be2-Hydroxypropyl-gamma-cyclodextrin, methyl-β-cyclodextrin,hydroxypropyl-β-cyclodextrin, or any derivative thereof. Cyclodextrinsare relatively large cyclic carbohydrates that are conical in shape.This structure can form supramolecular inclusion host-guest particles,wherein cyclodextrin is the host molecule and the active ingredient isthe guest molecule residing within the hydrophobic core of cyclodextrin.The host-guest complex may be generated by physically mixing thecomplexing agent (e.g., cyclodextrin molecule) with the activeingredient.

Those skilled in the art will appreciate that both natural andchemically modified cyclodextrins are readily available in the art andmay be used in the present invention to increase the biological activityof an active ingredient (see “Comprehensive Supramolecular Chemistry”Volume 3, edited by József Szejtili and Tetsuo Osa, published byElsevier Science Inc., New York, N.Y.). Naturally occurringcyclodextrins include α-, β-, and γ-cyclodextrins (Pagington, Chemistryin Britain, 23:455 (1987); Parrish, Cyclodextins-A Review, SteringOrganics Ltd. Newcastel-Upon-Tyne. England; Szejtli, CyclodextrinTechnology: Topics in Inclusion Science, Kluwer Academic Publishers(1988)). Modifications of natural cyclodextrins can also easily be madeand include, for example, glucosyl-α-cyclodextrin,maltosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, andmaltosyl-β-cyclodextrin.

Those skilled in the art will further appreciate that many differentchemical moieties may be introduced into the cyclodextrin molecule andsuch chemically modified cyclodextrins are readily available (see, e.g.,Yoahida et al., Int. Pharm., 46:217 (1988); Muller et al., J. Pharm.Sci., 75(6): June 1986; Irie et al., Pharm. Res., No. 11, p. 713(1988)). In one example, chemically modified cyclodextrins may begenerated by reaction of the hydroxyl groups lining the upper and lowerridges of the toroid of cyclodextrin with, for example, methyl,hydroxyethyl, hydoxylpropyl, carboxymethyl, or acetyl. Each cyclodextrinhydroxyl group differs in its chemical reactivity so that the reactionprocess produces an amorphous mixture of thousands of positional andoptical isomers. The hydroxypropyl-β-cyclodextrin system is a highlycomplex mixture of various isometric forms of variously substitutedβ-cyclodextrin derivatives. This property of amorphousness is importantto certain physiochemical properties of the chemically modifiedcyclodextrins and has beneficial effects on aqueous solubility andtoxicity of the crystalline parent molecule (Yoshida et al., supra;Muller et al., supra; Irie et al., supra; Muller et al., Pharm Res.,10:309 (1985)).

Those skilled in the art will appreciate that complexing agents such ascyclodextrin may be used to optimize the bioactivity or efficacy of anactive ingredient. Furthermore, complexing agents can be used tostabilize the NSAID and the antibiotic by building a complex. Withoutthe complexing agent, such as cyclodextrin, the NSAID or antibiotic willoxidize. Formulations may be further optimized by derivatization of acyclodextrin molecule to optimize the concentration, storage,manufacturing requirements, or route of administration of the activeingredient.

Typical ophthalmologically acceptable carriers for the compositionsdisclosed herein include, for example, water, mixtures of water andwater-miscible solvents such as lower alkanols or aralkanols, vegetableoils, polyalkylene glycols, petroleum based jelly, ethyl cellulose,ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropylmyristate, and other conventionally employed acceptable carriers. Insome embodiments, the pharmaceutical composition also contains non-toxicauxiliary substances such as emulsifying, preserving, wetting agents,bodying agents and the like, such as for example, polyethylene glycols200, 300, 400, and 600, carbowaxes 1,000, 1,500, 4,000, 6,000, and10,000, antibacterial components such as quaternary ammonium compounds,phenylmercuric salts known to have cold sterilizing properties and whichare non-injurious in use, thimerosal, benzalkonium chloride, methyl andpropyl paraben, benzyldodecinium bromide, benzyl alcohol, phenylethanol,buffering ingredients such as sodium chloride, sodium borate, sodiumacetate, or gluconate buffers, and other conventional ingredients suchas dextrose, maltodextrin, glycerol, ethanol, sorbitan monolaurate,triethanolamine, polyoxyethylene sorbitan monopalmitylate, dioctylsodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetra-acetic acid, and the like. Additionally, suitable ophthalmicvehicles are used as carrier media in some embodiments for the presentpurpose including conventional phosphate buffer vehicle systems,isotonic boric acid vehicles, isotonic sodium chloride vehicles,isotonic sodium borate vehicles and the like. Optionally, in someembodiments, the compositions further comprise other additives such as,for example, inert gases (e.g., nitrogen, helium, neon, argon, krypton,xenon).

The pharmaceutical composition is formulated in a number of differentways according to the present disclosure. Ophthalmic formulationsinclude but are not limited to ocular injections such as intravitreal,subtenons, subconjunctival, periocular, retrobulbar injections; topicalophthalmic aqueous solutions, such as suspensions, ointments, and gels;intraocular biodegradable and non-biodegradable implants; implants thatare inserted through incisions made in the eye wall or sutured aroundthe globe of the eye; tack for intraocular drug delivery; andbioadhesive ophthalmic inserts.

In some topical embodiments involving ophthalmic administration, thepresently disclosed compositions take the form of solutions, gels,ointments, suspensions, or solid inserts, formulated so that a unitdosage comprises an effective amount of each active component (i.e., atleast two of corticosteroid, NSAID, and antibiotic) or some submultiplethereof.

In cataract surgery, the most prevalent side effect (more than 80% ofpatients) is ocular discomfort due to dry eyes. Thus, artificial tearproducts are often given to patients to relieve ocular discomfort. Themajority of commercial artificial tears contain viscoelastic polymerssuch as hypromellose (hydroxypropylmethylcellulose), carbomer, orhyaluronic acid as viscosifying agents. In some embodiments thepresently disclosed compositions include one or more viscosifying agentsto reduce post-operative ocular discomfort. In some embodiments, theviscosifying agent is a viscoelastic polymer. Non-limiting examples ofviscoelastic polymers useful in the presently disclosed compositions andmethods include, but are not limited to, polymeric cellulose,polysaccharides, polyacrylic acid, polymeric alcohol such aspolyvinylalcohol, hyaluronic acid, derivatives, and salts thereof.

In some embodiments, the composition is a topical eye gel. Aviscosifying agent is needed to create a gel formulation. However, manyviscosifying agents are ionogenic (e.g. polyacrylic acid, which is acarbomer) and thus incompatible with certain NSAIDs, such as diclofenac.Moreover, some viscosifying agents (e.g. kollidon) are unsuitable toreach a viscosity required to make a stable suspension for this purpose.As a result, no ophthalmic formulations containing diclofenac exist onthe market as gel formulations. As disclosed herein, methylcellulose isan effective viscosifying agent for compositions comprising diclofenac.Thus, in some embodiments, the viscosifying agent within the presentlydisclosed compositions is methylcellulose (MC).

The concentration of the viscosifying agent is critical. Prednisoloneacetate is micronized and very poorly water soluble and is thereforepresent in particulate form and sediments in liquid solutions withinless than one minute. Thus, the viscosity of the composition must behigh enough to form a stable gel that does not allow sedimentation ofprednisolone acetate. Further, the viscosity must be high enough tocause a significant clinical effect, meaning the retention of the eyegel on the eye should be good enough in order to be efficacious and toreduce the dosage of at least one of the active ingredients. On theother side, the viscosity must not be too high so as to remaindroppable. Further, a too high viscosity generally can lead to oculardiscomfort (stickiness, impairment of vision similar to eye ointments),which should be avoided.

In some embodiments, the concentration of the viscosifying agent (e.g.,methylcellulose) is between about 1% and about 5% (weight/volume) of thetotal volume of the presently disclosed compositions, including, but notlimited to, 1% (w/v), 1.5% (w/v), 2% (w/v), 2.5% (w/v), 3% (w/v), 3.5%(w/v), 4% (w/v), 4.5% (w/v), and 5% (w/v). In particular embodiments,the presently disclosed compositions comprise between about 2% and about4% of a viscosifying agent (e.g., methylcellulose).

In another embodiment, the viscosifying agent is included in an amountof about 1.0% (w/v) to about 4.50% (w/v), or from 1.50% (w/v) to 4.0%(w/v), or 2.0% (w/v) to 3.50% (w/v), or from 2.5% (w/v) to 3.0% (w/v).

In a further embodiment, the viscosifying agent is included in an amountof about 1.0% (w/v)±0.50 (w/v), 1.5% (w/v)±1.0 (w/v), 2.0% (w/v)±1.5(w/v), 2.5% (w/v)±2.0 (w/v), 3.0% (w/v)±2.5 (w/v), or about 3.5%(w/v)±3.0 (w/v), or about 4.0% (w/v)±3.50 (w/v), or about 4.5% (w/v)±4.0(w/v).

In an alternative embodiment, the viscosifying agent is included in anamount of about 1.0% (w/v) to about 1.50% (w/v), or from 1.5% (w/v) to2.0% (w/v), or 2.0% (w/v) to 2.5% (w/v), or 2.5% (w/v) to 3.0% (w/v), or3.0% (w/v) to 3.50% (w/v), or 3.50% (w/v) to 4.0% (w/v), or 4.0% (w/v)to 4.5% (w/v), or from 4.5% (w/v) to 5.0% (w/v). In another embodiment,the viscosifying agent is included in an amount of about 0.75% (w/v) toabout 1.25% (w/v), or from 1.25% (w/v) to 1.75% (w/v), or 1.75% (w/v) to2.25% (w/v), or 2.25% (w/v) to 2.75%, 2.75% (w/v) to 3.25% (w/v), or3.25% (w/v) to 3.75% (w/v), or 3.75% (w/v) to 4.25% (w/v), or 4.25%(w/v) to 4.75% (w/v), or from 4.75% (w/v) to 5.25% (w/v).

The presently disclosed pharmaceutical compositions also include, insome embodiments, a gum such as gellan gum, for example, at aconcentration of about 0.1 to about 2% by weight.

After surgery, eyes are sensitive to synthetic chemicals, therefore insome embodiments, the presently disclosed compositions are substantiallypreservative-free. As used herein, the term “preservative” refers to acompound that when added to a composition prevents the degradation ofcomponents of the composition through microbial growth or action orundesired chemical changes. In some of those embodiments wherein thecomposition is substantially preservative-free, inert gases may still bepresent.

The presently disclosed compositions can comprise multiple doses (i.e.,a multi-dose container) considering many patients with eye conditionsare advanced in age, making small single dose units difficult to handle.

III. Methods of Using the Ophthalmic Compositions

Methods of treating or preventing ophthalmic conditions in a subjectcomprise administering to a subject in need thereof an effective amountof the presently disclosed ophthalmic compositions.

The presently disclosed compositions, described above, are intended tobe administered topically by direct or indirect application to the eye.In various embodiments, as described above, the compositions are in theform of a gel, a liquid, a suspension, a solution, an ointment, a mist,or an aerosol.

In one embodiment, treatment includes the application or administrationof an ophthalmic composition as described herein to a subject, where thesubject has, or is at risk of developing an ophthalmic condition. Inanother embodiment, treatment includes the application or administrationof an ophthalmic composition comprising an NSAID and a corticosteroid toa subject where the subject is at risk of developing CME. In anotherembodiment, the treatment includes application or administration of anophthalmic composition comprising an NSAID and an antibiotic. In anotherembodiment, the treatment includes application or administration of anophthalmic composition comprising a corticosteroid and an antibiotic. Ina further embodiment, the composition comprises all three API, includingan NSAID, a corticosteroid, and an antibiotic. It should be appreciatedby one skilled in the art that treating a patient with a singlecomposition comprising a combination of an NSAID and a corticosteroid,or a combination of an NSAID and an antibiotic, or a combination of acorticosteroid and an antibiotic, or a combination of all three activeagents (e.g., NSAID, corticosteroid, and an antibiotic) has benefitsover treating patients with each therapy separately as it will increasepatient adherence to the treatment protocol leading potentially to areduction in the length of time needed to administer the drops, and aconcomitant reduction in medical cost.

In accordance with the present invention, the ophthalmic composition asdescribed herein can be used to promote a positive therapeutic responsewith respect to the ophthalmic condition. A “positive therapeuticresponse” with respect to the ophthalmic condition is intended toinclude an improvement in the disease that can be evidenced by, forexample, a delayed onset of clinical symptoms of the condition, areduction in severity of some or all clinical symptoms of the condition,a slower progression of the condition, an improvement in the overallhealth or well-being of the subject, or by other parameters well knownin the art that are specific to the particular condition.

In keeping with the scope of the present disclosure, the ophthalmiccomposition as described herein are administered to a human or otheranimal in accordance with the aforementioned methods of treatment in anamount sufficient to produce a therapeutic effect. In an embodiment, theophthalmic composition is administered to such a human or other animalin a conventional dosage form prepared by combining the ophthalmiccomposition described herein with a conventional pharmaceuticallyacceptable carrier according to known techniques. In accordance with oneembodiment, the ophthalmic composition is administered to such a humanor animal concurrently with another medication such as, but not limitedto, subconjunctival injection of triamcinolone acetonide and/or anintravitreal injection of bevacizumab. It will be recognized by one ofskill in the art that the form and character of the pharmaceuticallyacceptable carrier is dictated by the amount of active ingredient withwhich it is to be combined, the route of administration and otherwell-known variables.

In another embodiment, the ophthalmic composition as described herein isuseful in the prevention of various ophthalmic conditions. The term“prevention” is well known in the art and is defined hereinabove. Forexample, a subject suspected of being prone to suffer from a conditionas defined herein may, in particular, benefit from a prevention of thecondition. The subject may have a susceptibility or predisposition forthe condition, including but not limited to hereditary predisposition.Such a predisposition can be determined by standard assays, using, forexample, genetic markers or phenotypic indicators. In one embodiment, acondition to be prevented has not yet been diagnosed or cannot bediagnosed in the subject (for example, the subject does not show anyclinical or pathological symptoms). Thus, the term “prevention”therefore includes the use of the presently disclosed compositionsbefore any clinical and/or pathological symptoms are diagnosed ordetermined or can be diagnosed or determined by an attending physician.Prevention includes, without limitation, to avoid the condition fromoccurring in the subject that may be predisposed to the disease but doesnot yet experience or exhibit symptoms of the disease (prophylactic orpreventative care).

Patients with an increased risk of developing CME and/or ocularinflammation include but are not limited to those characterized by atleast one of the following characteristics:

-   -   prolonged surgery;    -   previous surgery;    -   young patients (younger than 50 years);    -   history of CME;    -   history of diabetes mellitus    -   history of uveitis;    -   history of intraocular inflammation;    -   existing additional ocular diseases;    -   diabetic retinopathy; and    -   retinal venocclusion.

The amount of ophthalmic preparation to be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. The compositionis in one embodiment administered as a single dose. In otherembodiments, the compositions described herein are administered asmultiple doses. Dosage regimens also can be adjusted to provide theoptimum desired response (e.g., a therapeutic or prophylactic response).In one embodiment, the compositions described herein are administered atspecific fixed or variable intervals, e.g., once a day, or on an “asneeded” basis.

The dosage regimen will be determined by the attending physician andclinical factors. As is well known in the medical arts, dosages for anyone patient depends upon many factors, including the patient's size,body surface area, age, the particular compound to be administered, sex,time and route of administration, general health, and other drugs beingadministered concurrently. Generally, the regimen as a regularadministration of the pharmaceutical composition comprising the hereindefined should be, e.g., in a range as described below. Progress can bemonitored by periodic assessment.

In one embodiment, the presently disclosed pharmaceutical compositionsare liquid in form and administered as 1 drop into the eye as a singledose. In other embodiments, the presently disclosed compositions areadministered as 2 drops, 3 drops, 4 drops, 5 drops, 6 drops, 7 drops, 8drops, 9 drops, 10 drops, or more into the eye as a single dose. Abouttwenty drops are equal to 1 mL of fluid.

In some embodiments, each dose of the pharmaceutical composition isadministered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, or 20 times per day. In some embodiments, the pharmaceuticalcomposition is administered more than 20 times per day. In otherembodiments, the presently disclosed compositions are administered at adose of one drop between 1 and 6 times per day. In some embodiments, thecomposition is administered at a dose of one drop between 1 and 3 timesper day.

The presently disclosed compositions are used in some embodiments toprevent or treat ophthalmic conditions that result from ocular surgery,such as cataract surgery. In these embodiments, the compositions areadministered pre-operatively, peri-operatively, and/or post-operatively.In some of these embodiments, the ophthalmic composition is administeredat a dose of one drop between 1 and 3 times pre-operatively. In some ofthose embodiments wherein the composition is administeredpost-operatively, the dose is one drop between 1 and 6 times per day. Inparticular embodiments, the dose is one drop between 1 and 3 times perday, administered post-operatively. In particular embodiments, thepresently disclosed compositions are administered within the same day ofthe surgical procedure post-operatively and in some of theseembodiments, daily for up to 4-6 weeks following the surgery.

The composition is in some embodiments administered for short periods oftime or regularly for longer periods of time. In an embodiment, thecomposition is administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,or more days. In other embodiments, the composition is administeredregularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks. In anotherembodiment, the composition is administered regularly for 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, or more months. In an embodiment, thecomposition is administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,or more years. As used herein, the term “regularly” refers toadministration of the composition at regular or evenly spaced times orintervals over a period of time. For instance, the composition is in oneembodiment administered to a patient once daily for three years. Inother embodiments, the composition is administered to a patient onceevery other day for 5 years. It should be appreciated that the frequencyof administration is varied based on a number of factors, including, butnot limited to, the severity of disease, the overall health of thepatient, any additional medications the patient is taking, and whetherthe treatment is prophylactic or not. It should also be appreciated thatthe frequency of administration is adjustable at any point in thetreatment regimen.

In one embodiment, the composition comprising the ophthalmic preparationas described herein is used in combination with any known conventionaltherapy or prophylactic therapy for any of the eye conditions disclosedherein. Such conventional therapies and prophylactics are well known inthe art and the skilled person knows any such therapies.

Provided are also embodiments in which the ophthalmic composition isused in the manufacture of a medicament for treating or preventing anophthalmic condition in a subject in need thereof, wherein themedicament is used in a subject that has been pretreated or isconcurrently being treated with at least one other therapy. By“pretreated” or “pretreatment” is intended the subject has received oneor more other therapies prior to receiving the medicament comprising theophthalmic composition. “Pretreated” or “pretreatment” includes subjectsthat have been treated with at least one other therapy within 2 years,within 18 months, within 1 year, within 6 months, within 2 months,within 6 weeks, within 1 month, within 4 weeks, within 3 weeks, within 2weeks, within 1 week, within 6 days, within 5 days, within 4 days,within 3 days, within 2 days, or even within 1 day prior to initiationof treatment with the medicament comprising the ophthalmic composition.By “concurrent” or “concomitant” is intended the subject is receivingone or more other therapies while at the same time receiving themedicament comprising the ophthalmic composition. It is not necessarythat the subject was a responder to pretreatment with the prior therapyor therapies or a responder to the concurrent therapy or therapies.Thus, the subject that receives the medicament comprising the ophthalmiccomposition could have responded, or could have failed to respond, topretreatment with the prior therapy, or to one or more of the priortherapies where pretreatment comprised multiple therapies.

IV. Methods of Preparing Ophthalmic Compositions

Also disclosed herein are methods for preparing the presently disclosedcompositions comprising at least two of a corticosteroid, an NSAID, andan antibiotic. In those embodiments wherein the composition comprises anNSAID and an antibiotic, the preparation methods comprise separatelycomplexing the NSAID and the antibiotic with cyclodextrin. Cyclodextrinand/or other complexing agents can be used to stabilize the NSAID andthe antibiotic by building a complex. Without the complexing agent, suchas cyclodextrin, the NSAID or antibiotic will oxidize. In oneembodiment, the methods comprise preparing the composition in the formof a gel.

In an embodiment, the composition contains the following ingredientsshown in Table 1 below:

Concen- tration Strength range Material (%/weight) Function (w/v)Prednisolone 0.5% Active pharmaceutical 0.1-1.0% acetate ingredient(API) Diclofenac-Na * 0.01-0.1% API 0.01-0.15% Ofloxacin 0.3% API0.1-0.5% Methylcellulose** Approx 2-4% viscosifier 1-5% 2-hydroxypropyl-— For complexation gamma- of diclofenac cyclodextrin*** and ofloxacinMannitol  5% To adjust Osmotic pressure Specification 280-314 mosmol/kgSodium disulfite 0.02%  Antioxidant NaOH/HCL — For pH adjustmentSpecification 5.5-8.5 Water q.s. solvent * Due to the lower localtolerance of diclofenac, the concentration of diclofenac may need to bereduced from the commonly used 0.1% because diclofenac is present on thecornea for a longer time period with gel formulations versus eye dropformulations. The exact concentration will be determined in anon-clinical dose finding experiment. Prednisolone acetate and ofloxacinare both at their commonly used and approved concentrations. **The exactconcentration will be determined, but will likely lie within 2% and 4%methylcellulose. The viscosity has to be relatively high, otherwise thesuspension (prednisolone acetate is present in particulate form) is notstable. This is required if the product is sold in single dose units ortubes. ***2-Hydroxypropyl-gamma-cyclodextrin is complexed withdiclofenac and ofloxacin (two separate steps). The molar ratio ofcyclodextrin to the API is between 1:1 and 1:2 (2x cyclodextrin).

Diclofenac and ofloxacin are generally incompatible because exposure tooxygen causes oxygenation of diclofenac which in turn results indegradation of ofloxacin into ofloxacin-N-oxide (See European Patent No.EP0994693B1, which is incorporated herein in its entirety). To solvethis issue, ofloxacin and diclofenac are complexed in the describedembodiment separately with cyclodextrin and stored under conditions thatexclude oxygen and instead include inert gases, such as, for example,nitrogen, and/or argon.

In one embodiment, a method for preparing a composition comprisingprednisolone, diclofenac, and ofloxacin in a gel formulation comprisesthe steps of:

a) producing a methylcellulose gel to form Solution 1;

b) complexing ofloxacin with 2-hydroxypropyl-gamma-cyclodextrin to formSolution 2;

c) complexing diclofenac with 2-hydroxypropyl-gamma-cyclodextrin to formSolution 3;

d) combining Solutions 2 and 3 to form Solution 4;

e) adjusting pH of Solution 4 to range of between 5.5 to 8.5;

f) adding mannitol to Solution 4 to form Solution 5;

g) combining Solutions 1 and 5 to form Solution 6; and

h) adding prednisolone acetate to Solution 6.

Steps a)-c) are able to be performed in any order, and step a) isperformed before, simultaneously, or after any one of steps b)-f).

In one embodiment, the molar ratio of cyclodextrin to each of the NSAIDand antibiotic is between 1:1 and 1:2. In particular embodiments, themolar ratio of 2-hydroxypropyl-gamma-cyclodextrin to diclofenac orofloxacin is between 1:1 and 1:2 (2× cyclodextrin).

In some embodiments, the method further comprises distributing theprepared composition into container(s) and overlaying the compositionwith an inert gas to exclude oxygen, followed by sealing of thecontainer to entrap the inert gas therein. As used herein, and “inertgas” is one that does not chemically react with any component of thepresently disclosed compositions under routine storage conditions.Non-limiting examples of inert gases that are suitable for use in thepresently disclosed methods and compositions are nitrogen, helium, neon,argon, krypton, and xenon.

All of the references cited above, as well as all references citedherein, are incorporated herein by reference in their entireties.

While the described methods and compositions are illustrated anddescribed in detail in above, such illustration and description are tobe considered illustrative or exemplary and not restrictive. It will beunderstood that changes and modifications may be made by those ofordinary skill within the scope and spirit of the following claims. Inparticular, the present disclosure is intended to encompass any furtherembodiments including any combination of features from differentindividual embodiments described above and below. For instance, includedin the disclosure are embodiments such as adding antibiotics to theophthalmic composition, using other corticosteroids, and/or other NSAIDsnot described herein but otherwise known in the art, and administratingthese APIs together with at least one other medication for optimizingtreatment efficacy (e.g., administering concurrently withsubconjunctival injection of 40 mg triamcinolone acetonide).

The following illustrative non-limiting examples provide a betterunderstanding of the disclosed compositions and methods and of theirmany advantages. The following examples are included to demonstratepreferred embodiments. It should be appreciated by those of skill in theart that the techniques disclosed in the examples which follow representtechniques that function well for their intended purpose, and thus areconsidered to constitute preferred modes for its practice, but areotherwise not limiting and substitutable by other known means ofachieving the same outcomes. However, those of skill in the art should,in light of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLES Example 1: An Ophthalmic Preparation

This example illustrates an embodiment of the presently disclosedophthalmic preparations. This particular preparation incorporates theingredients and concentrations thereof as shown in Table 2 below.

TABLE 2 Concen- Strength tration Material ( %/weight) Function rangePrednisolone 0.5% Active pharmaceutical 0.1-1.0% acetate ingredient(API) Diclofenac-Na * 0.01-0.1%   API 0.01-0.15% Ofloxacin 0.3% API0.1-0.5% Methylcellulose** Approx 2-4% viscosifier 1-5% 2-Hydroxypropyl-— For complexation gamma- of diclofenac cyclodextrin*** and ofloxacinMannitol  5% To adjust Osmotic pressure Specification 280-314 mosmol/kgSodium disulfite 0.02%  Antioxidant NaOH/HCL — For pH adjustmentSpecification 5.5-8.5 Water q.s. solvent * Due to the lower localtolerance of diclofenac, the concentration of diclofenac may need to bereduced from the commonly used 0.1% because diclofenac is present on thecornea for a longer time period with gel formulations versus eye dropformulations. The exact concentration will be determined in anon-clinical dose finding experiment. Prednisolone acetate and ofloxacinare both at their commonly used and approved concentrations. **The exactconcentration will be determined, but will likely lie within 2% and 4%methylcellulose. The viscosity has to be relatively high, otherwise thesuspension (prednisolone acetate is present in particulate form) is notstable. This is required if the product is sold in single dose units ortubes. ***2-Hydroxypropyl-gamma-cyclodextrin is complexed withdiclofenac and ofloxacin (two separate steps). The molar ratio ofcyclodextrin to the API is between 1:1 and 1:2 (2x cyclodextrin).

For a representative 500 g batch, the concentrations of variouscomponents of an exemplary embodiment of the disclosed compositions areshown in Table 3 below:

TABLE 3 Final g/500 g concentration Material batch (%/weight)Prednisolone acetate 2.5 0.5% Diclofenac-Na 0.5 0.1% 2-Hydroxypropyl-2.48 gamma-cyclodextrin* Ofloxacin 1.5 0.3% 2-Hydroxypropyl- 6.55gamma-cyclodextrin** Methylcellulose 17.5 3.5% Mannitol 25   5% Sodiumdisulfite 0.1 0.02%   NaOH/HCL — Water 438.87 q.s. Total 500 *Fordiclofenac-Na complexation. **For ofloxacin complexation.

Example 2: Anti-Inflammatory Efficacy and Intraocular Concentrations ofPrednisolone Acetate-Diclofenac Eye Gel Vs. Prednisolone Acetate EyeDrops and Diclofenac Eye Drops as Single Preparations

A sufficiently high number of adequate laboratory animals (e.g. rabbitsor pigs, at least five animals per group) are used in this experimentsuch that statistical significance is achieved in any collected data.Ocular inflammation is experimentally induced in all animals by knownmethods. Animals are then divided into four treatment groups. Group 1 istreated with ophthalmic prednisolone-diclofenac eye gel. Group 2 istreated with the same concentration of ophthalmic prednisolone eye dropsas used in Group 1. Group 3 is treated with the same concentration ofophthalmic diclofenac eye drops as used in Group 1. Group 4 is treatedwith the same concentration of ophthalmic diclofenac eye drops andprednisolone eye drops, administered as two separate formulations, asused in Group 1. Group 5 is mock treated (matrix only). The experimentis repeated using different concentrations of prednisolone acetate anddiclofenac in eye gel formulation. After different time points, ocularinflammation in all treated animals is assessed using standardparameters, such as immigration of inflammatory cells into the eye,presence of inflammatory mediators, etc. As a second readout,intraocular fluid is drawn from laboratory animals at different timepoints to analyse intraocular API concentrations.

Results: the experiment is designed to show that the single preparationof the combination of prednisolone, acetate, and diclofenac is superiorin its anti-inflammatory efficacy as compared to the single preparationsof prednisolone, acetate, or diclofenac alone. This experiment may alsoshow that, unexpectedly, the single preparation of the combination ofprednisolone, acetate, and diclofenac shows not an additive, butsynergistic effect, i.e. the level of inhibition of inflammation ishigher than one of skill in the art would predict that the addition ofthe inhibitory effects would be for prednisolone, acetate, anddiclofenac as compared with these APIs administered sequentially asseparate formulations. Also, this experiment is designed to show thatthe intraocular concentrations of API are will be higher afteradministration of eye gel preparations as compared to eye dropformulations and thus, concentrations of APIs may be reduced whenformulated as an eye gel in order to reach the equivalent clinicaleffect as eye drops.

Example 3: Local Tolerability of PrednisoloneAcetate-Diclofenac-Ofloxacin Eye Gel Vs. Prednisolone Acetate,Diclofenac, Ofloxacin Eye Drops as Single Preparations on Human Corneas

The effect of different preparations is tested on human corneas toascertain ocular corneal toxicity.

Test drug 1: Ophthalmic prednisolone acetate-diclofenac-ofloxacin eyegel

Test drug 2: Ophthalmic prednisolone acetate eye drops

Test drug 3: Ophthalmic diclofenac eye drops

Test drug 4: Ophthalmic ofloxacin eye drops

Treatment group 5: Ophthalmic prednisolone acetate eye drops, ophthalmicdiclofenac eye drops, and ophthalmic ofloxacin eye drops, administeredas three separate preparations

Test drug 5-x: Ophthalmic prednisolone acetate-diclofenac-ofloxacin eyegel with different concentrations of APIs.

Corneal toxicity is to be assessed upon administration of the variousformulations using standard techniques known in the art, such as cellcultures of both presumed target cells and non-target cells for theassessment of ocular irritation. The experiment is designed to show thatthe eye gel formulation is tolerated better than the eye dropformulations and causes less local side effects.

Example 4: Local Tolerability of PrednisoloneAcetate-Diclofenac-Ofloxacin Eye Gel Vs. Prednisolone Acetate,Diclofenac, Ofloxacin Eye Drops as Single Preparations in HealthyVolunteers

A sufficiently high number of human healthy adult volunteers are to beincluded in this study. Group 1 is treated with ophthalmicprednisolone-diclofenac-ofloxacin eye gel. Group 2 is treated with thesame concentration of ophthalmic prednisolone eye drops as used inGroup 1. Group 3 is treated with the same concentration of ophthalmicdiclofenac eye drops as used in Group 1. Group 4 is treated with thesame concentration of ophthalmic ofloxacin eye drops as used in Group 1.Group 5 is treated with the same concentration of ophthalmicprednisolone eye drops, ophthalmic diclofenac eye drops, and ophthalmicofloxacin eye drops as used in Group 1, in three separate preparations.Group 6 is mock treated (matrix only). Ocular discomfort uponadministration is determined. Ocular adverse effects and systemicadverse events (blood sugar levels) after multiple administrations (2weeks of daily treatments) are compared between the groups.

The experiment is designed to show that the eye gel formulation istolerated better than the eye drop formulations and causes less systemicside effects.

Example 5: Efficacy, Ocular Tolerance, Patient Compliance and Incidenceof CME after Cataract Surgery Using Perioperative PrednisoloneAcetate-Diclofenac-Ofloxacin Triple Combination Vs. Standard Treatment

A sufficiently high number of human patients undergoing cataract surgeryregarded as at risk of developing CME are included in this study. Theseinclude but are not limited to the following: prolonged surgery,previous surgery, young patients (younger than 50 years), history ofCME, history of uveitis, history of intraocular inflammation, existingadditional ocular diseases, diabetic retinopathy, and retinalvenocclusion.

Treatment drug 1: prednisolone acetate-diclofenac-ofloxacin eye geltriple combination

Treatment drug 2: prednisolone acetate eye drops+ofloxacin eyedrops+ofloxacin eye drops+artificial tears

Patients are randomized to either treatment group. Treatment is given topatients standard peri- and post-surgical care after cataract surgery.Post-surgery, treatment is administered the same day as the surgicalprocedure and for 4-6 weeks daily. Patients are followed up daily forapproximately 4-6 weeks. At defined time points, patients are examinedfor certain parameters such as visual acuity, macular thickness,endothelial cell density, central corneal thickness, established CME aswell as subjective parameters such as eye discomfort, ocular pain andpatient compliance.

The primary readouts expected from this study include incidence of CME,ocular tolerance, patient compliance, direct and indirect signs ofinflammation. The secondary readouts expected from this study includepatient compliance with the study drug.

This experiment is designed to show that patients treated with Treatmentdrug 1 will exhibit equal or lower incidence of CME and retinalswelling, equal or better inflammation suppression, better patientcompliance as well as equal or better ocular tolerance including eyediscomfort and pain as compared to those patients that were treated withthe individual drugs.

Example 6: Efficacy in CME Prevention after Cataract Surgery UsingPerioperative Prednisolone Acetate-Diclofenac Combination Vs. DiclofenacEye Drops

A sufficiently high number of human patients undergoing cataract surgeryregarded as at risk of developing CME are to be included in this study.These include but are not limited to the following: prolonged surgery,previous surgery, young patients (younger than 50 years), history ofCME, history of uveitis, history of intraocular inflammation, history ofdiabetes mellitus, existing additional ocular diseases, diabeticretinopathy, and retinal venocclusion.

Treatment drug 1: prednisolone acetate-diclofenac-eye drops doublecombination

Treatment drug 2: diclofenac-eye drops

Patients will be randomized to either treatment group. Treatment isgiven to patients in standard peri- and post-surgical care aftercataract surgery. For those patients in post-surgery, treatment is to beadministered the same day as the surgical procedure and for 4-6 weeksdaily. Patients are followed up daily for approximately 4-6 weeks. Atdefined time points, patients are then examined for certain parameterssuch as visual acuity, macular thickness, endothelial cell density,central corneal thickness, established CME as well as subjectiveparameters such as eye discomfort, ocular pain and patient compliance.

Primary readouts include an estimation of the incidence of CME, as wellas observations concerning direct and indirect signs of inflammation.

This experiment is designed to show that patients treated with Treatmentdrug 1 are expected to exhibit a lower incidence of CME and retinalswelling, and equal or better inflammation suppression, as compared tothose patients which were treated with treatment drug 2.

Example 7: Efficacy in CME Prevention after Cataract Surgery UsingPerioperative Dexamethasone-Bromfenac Combination Vs. Bromfenac EyeDrops

A sufficiently high number of human patients undergoing cataract surgeryregarded as at risk of developing CME are to be included in this study.These patients may include, but are not limited to, the followingpatient histories and profiles: prolonged surgery, previous surgery,young patients (younger than 50 years), history of CME, history ofuveitis, history of intraocular inflammation, history of diabetesmellitus, existing additional ocular diseases, diabetic retinopathy, andretinal venocclusion.

Treatment drug 1: bromfenac-eye drops

Treatment drug 2: dexamethasone-bromfenac-eye drops double combination

Treatment drug 3: dexamethasone-bromfenac-eye drops double combinationand a subconjunctival injection of 40 mg triamcinolone acetonide

Treatment drug 4: dexamethasone-bromfenac-eye drops double combinationand an intravitreal injection of 1.25 mg bevacizumab

Treatment drug 5: dexamethasone-bromfenac-eye drops double combinationand a subconjunctival injection of 40 mg triamcinolone acetonide and anintravitreal injection of 1.25 mg bevacizumab.

Patients are to be randomized to all of the treatment groups. Treatmentis given to patients in standard peri- and post-surgical care aftercataract surgery. For those patients in the post-surgery group,treatment is administered the same day as the surgical procedure and forseveral weeks daily. Patients are to return to the physician forfollowed up visits that include direct observations of condition dailyfor approximately 6-12 weeks.

Primary indicators expected from this study include incidence of CME aswell as observations of direct and indirect signs of inflammation.

The experiment is designed to show that patients treated with Treatmentdrug 1 exhibit a higher incidence of CME and other signs of inflammationand ocular conditions as compared to those patients who were treatedwith treatment drugs 2, 3, 4, and 5.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended claimsdisclosed herein. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

That which is claimed:
 1. A composition comprising a non-steroidalanti-inflammatory drug (NSAID) and a corticosteroid.
 2. The compositionof claim 1, wherein the concentration of the NSAID is between 0.05% and0.5% (weight/volume) of the total volume of the composition.
 3. Thecomposition of claim 1 or 2, wherein the NSAID is one or more ofdiclofenac, ketorolac tromethamine, bromfenac, nepafenac, derivativesthereof, and salts thereof.
 4. The composition of claim 1, wherein theNSAID is diclofenac, a salt thereof, and/or a combination thereof. 5.The composition of claim 4, wherein the concentration of diclofenac isbetween 0.05% and 0.2% (weight/volume) of the total volume of thecomposition.
 6. The composition of claim 4, wherein the concentration ofdiclofenac is about 0.1% (weight/volume) of the total volume of thecomposition.
 7. The composition of claim 1, wherein the NSAID isbromfenac, a salt thereof, and/or a combination thereof.
 8. Thecomposition of claim 7, wherein the concentration of bromfenac isbetween 0.05% and 0.2% (weight/volume) of the total volume of thecomposition.
 9. The composition of claim 7, wherein the concentration ofbromfenac is about 0.09% (weight/volume) of the total volume of thecomposition.
 10. The composition of claim 1, wherein the concentrationof the corticosteroid is between 0.05% and 2% (weight/volume) of thetotal amount of the composition.
 11. The composition of claim 1, whereinthe corticosteroid is one or more of prednisolone, dexamethasone,difluprednate, loteprednol etabonate, fluorometholone, derivativesthereof, and salts thereof.
 12. The composition of claim 1, wherein thecorticosteroid is prednisolone or a salt or derivative thereof.
 13. Thecomposition of claim 12, wherein the prednisolone salt is prednisoloneacetate.
 14. The composition of claim 12 or 13, wherein theconcentration of prednisolone or prednisolone acetate is between 0.25%and 1% (weight/volume) of the total amount of the composition.
 15. Thecomposition of claim 12 or 13, wherein the concentration of prednisoloneor prednisolone acetate is about 0.5% (weight/volume) of the totalamount of the composition.
 16. The composition of claim 1, wherein thecorticosteroid is dexamethasone or a salt or derivative thereof.
 17. Thecomposition of claim 16, wherein the concentration of dexamethasone or asalt or derivative thereof is between 0.05% and 0.5% (weight/volume) ofthe total amount of the composition.
 18. The composition of claim 16 or17, wherein the concentration of dexamethasone or a salt or derivativethereof is about 0.1% (weight/volume) of the total amount of thecomposition.
 19. The composition of any one of claims 1-18, wherein thecomposition further comprises an antibiotic.
 20. The composition ofclaim 19, wherein the concentration of the antibiotic is between 0.1%and 1% (weight/volume) of the total volume of the composition.
 21. Thecomposition of claim 19 or 20, wherein the antibiotic is a broadspectrum antibiotic.
 22. The composition of claim 19 or 20, wherein theantibiotic is a fluoroquinolone.
 23. The composition of claim 19 or 20,wherein the antibiotic is one or more of ofloxacin, moxifloxacin,ciprofloxacin, levofloxacin, besifloxacin, fluoroquinolone, derivativesthereof, and salts thereof
 24. The composition of claim 19, wherein theantibiotic is ofloxacin.
 25. The composition of claim 24, wherein theconcentration of ofloxacin is between 0.2% and 0.5% (weight/volume) ofthe total volume of the composition.
 26. The composition of claim 24,wherein the concentration of ofloxacin is about 0.3% (weight/volume) ofthe total volume of the composition.
 27. The composition of any one ofclaims 1-26, wherein the composition further comprises a complexingagent.
 28. The composition of claim 27, wherein the complexing agent iscyclodextrin or a derivative thereof.
 29. The composition of claim 27,wherein the complexing agent is 2-Hydroxypropyl-gamma-cyclodextrin. 30.The composition of any one of claims 1-29, wherein the compositionfurther comprises a viscosifying agent.
 31. The composition of claim 1,wherein the composition is formulated as viscous eye drops, an eye gel,eye cream, or eye ointment.
 32. The composition of claim 1, wherein thecomposition is formulated as an eye gel.
 33. The composition of claim30, wherein the viscosifying agent is a viscoelastic polymer.
 34. Thecomposition of claim 33, wherein the viscoelastic polymer is one or moreof polymeric cellulose, polysaccharides, polyacrylic acid, polymericalcohol, hyaluronic acid, derivatives thereof, and salts thereof. 35.The composition of claim 34, wherein the polymeric alcohol ispolyvinylalcohol.
 36. The composition of claim 30, wherein theviscosifying agent is methylcellulose.
 37. The composition of claim 36,wherein the concentration of methylcellulose is between 1% and 5%(weight/volume) of the total volume of the composition.
 38. Thecomposition of claim 36, wherein the concentration of methylcellulose isbetween 2% and 4% (weight/volume) of the total volume of thecomposition.
 39. A composition comprising a corticosteroid, anon-steroidal anti-inflammatory drug (NSAID), an antibiotic, andoptionally a viscosifying agent, wherein the composition is formulatedas an eye gel.
 40. The composition of claim 39, wherein theconcentration of the corticosteroid is between 0.05% and 2%(weight/volume) of the total amount of the composition.
 41. Thecomposition of claim 39 or 40, wherein the corticosteroid is one or moreof prednisolone, dexamethasone, difluprednate, loteprednol etabonate,fluorometholone, derivatives thereof, and salts thereof.
 42. Thecomposition of claim 41, wherein the corticosteroid is prednisolone, aderivative thereof, and/or a salt thereof.
 43. The composition of claim42, wherein the prednisolone salt is prednisolone acetate.
 44. Thecomposition of claim 42 or 43, wherein the concentration of theprednisolone, derivative thereof, and salt thereof is between 0.25% and1% (weight/volume) of the total volume of the composition.
 45. Thecomposition of claim 42, wherein the concentration of the prednisolone,derivative thereof, and salt thereof, is about 0.5% (weight/volume) ofthe total volume of the composition.
 46. The composition of any one ofclaims 39-45, wherein the concentration of the NSAID is between 0.05%and 0.5% (weight/volume) of the total volume of the composition.
 47. Thecomposition of any one of claims 39-46, wherein the NSAID is one or moreof diclofenac, ketorolac tromethamine, bromfenac, nepafenac, derivativesthereof, and salts thereof.
 48. The composition of claim 47, wherein theNSAID is diclofenac, a derivative thereof, or a salt thereof.
 49. Thecomposition of claim 48, wherein the concentration of the diclofenac,derivative thereof, and salt thereof, is between 0.05% and 0.2%(weight/volume) of the total volume of the composition.
 50. Thecomposition of claim 48, wherein the concentration of the diclofenac,derivative thereof, and salt thereof, is about 0.1% (weight/volume) ofthe total volume of the composition.
 51. The composition of any one ofclaims 39-50, wherein the concentration of the antibiotic is between0.1% and 1% (weight/volume) of the total volume of the composition. 52.The composition of any one of claims 39-51, wherein the antibiotic is abroad spectrum antibiotic.
 53. The composition of any one of claims39-51, wherein the antibiotic is a fluoroquinolone.
 54. The compositionof any one of claims 39-51, wherein the antibiotic is one or more ofofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, besifloxacin,derivatives thereof, and salts thereof.
 55. The composition of claim 54,wherein the antibiotic is ofloxacin, a derivate thereof, and/or a saltthereof.
 56. The composition of claim 55, wherein the concentration ofthe ofloxacin, a derivate thereof, and a salt thereof, is between 0.2%and 0.5% (weight/volume) of the total volume of the composition.
 57. Thecomposition of claim 55, wherein the concentration of the ofloxacin, aderivate thereof, and a salt thereof, is about 0.3% (weight/volume) ofthe total volume of the composition.
 58. The composition of any one ofclaims 39-57, wherein the viscosifying agent is a viscoelastic polymer.59. The composition of claim 58, wherein the viscoelastic polymer is oneor more of polymeric cellulose, polysaccharides, polyacrylic acid,polymeric alcohol, hyaluronic acid, derivatives thereof, and saltsthereof.
 60. The composition of claim 59, wherein the polymeric alcoholis polyvinylalcohol.
 61. The composition of any one of claims 39-59,wherein the viscosifying agent is methylcellulose.
 62. The compositionof claim 61, wherein the concentration of methylcellulose is between 1%and 5% (weight/volume) of the total volume of the composition.
 63. Thecomposition of claim 62, wherein the concentration of methylcellulose isbetween 2% and 4% (weight/volume) of the total volume of thecomposition.
 64. The composition of any one of claims 1-63, wherein thecomposition further comprises a pharmaceutically acceptable carrier. 65.The composition of any one of claims 1-64, wherein the composition issubstantially preservative-free.
 66. The composition of any one ofclaims 1-65, wherein the composition is provided as a single dose unit.67. The composition of any one of claims 1-65, wherein the compositionis provided in a multi-dose container.
 68. A method of treating and/orpreventing an ophthalmic condition in a subject, the method comprisingtopically administering an effective amount of the composition of anyone of claims 1-67 to an eye of a subject in need thereof.
 69. Themethod of claim 68, wherein the ophthalmic condition is at least one ofocular inflammation and ocular infection.
 70. The method of claim 68 or69, wherein the composition is administered at least one of peri- andpost-operative to ocular surgery.
 71. The method of claim 70, whereinthe ocular surgery is cataract surgery.
 72. The method of any one ofclaims 69-71, wherein the ophthalmic condition comprises one or more ofcystoid macula edema (CME), ocular pain after surgery, ocular discomfortafter surgery, and both ocular pain and ocular discomfort after surgery.73. The method of claim 68, wherein the subject is at risk of at leastone of CME and ocular inflammation.
 74. The method of claim 73, whereinthe subject: a) has had a prolonged surgery; b) has had a previoussurgery; c) is younger than 50 years; d) was previously diagnosed with,or had symptoms of, CME; e) was previously diagnosed with, or hadsymptoms of, diabetes mellitus; f) was previously diagnosed with, or hadsymptoms of, uveitis; g) was previously diagnosed with, or had symptomsof, intraocular inflammation; h) was previously diagnosed with, or hadsymptoms of, additional ocular diseases; i) was previously diagnosedwith, or had symptoms of, diabetic retinopathy; and/or j) was previouslydiagnosed with, or had symptoms of, retinal venocclusion.
 75. The methodof any one of claims 69-74, wherein the composition is administered at adose of one drop 1 to 6 times per day.
 76. The method of claim 75,wherein the dose is one drop 1 to 3 times pre-operatively.
 77. Themethod of claim 75, wherein the dose is one drop 1 to 6 times per daypost-operatively.
 78. The method of claim 75, wherein the dose is onedrop 1 to 3 times per day post-operatively.
 79. The method of any one ofclaims 69 to 78, wherein the composition is administered concurrentlywith at least one other medication.
 80. The method of any one of claims69 to 78, wherein the composition is administered concurrently with asubconjunctival injection of triamcinolone acetonide.
 81. The method ofclaim 80, wherein the triamcinolone acetonide is administered at a doseof 40 mg.
 82. The method of claim 79, wherein the composition isadministered concurrently with an intravitreal injection of bevacizumab.83. The method of claim 82, wherein the bevacizumab is administered at adose of 1.25 mg.
 84. The method of claim 79, wherein the composition isadministered concurrently with a subconjunctival injection oftriamcinolone acetonide and an intravitreal injection of bevacizumab.85. The method of claim 84, wherein the triamcinolone acetonide isadministered at a dose of 40 mg and the bevacizumab is administered at adose of 1.25 mg.
 86. A method for preparing a composition comprisingprednisolone, diclofenac, and ofloxacin in a gel formulation, the methodcomprising: producing a methylcellulose gel to form Solution 1;complexing ofloxacin with gamma-cyclodextrin to form Solution 2;complexing diclofenac with gamma-cyclodextrin to form Solution 3;combining Solutions 2 and 3 to form Solution 4; adding mannitol toSolution 4 to form Solution 5; Solutions 1 and 5 to form Solution 6; andadding prednisolone acetate to Solution 6, thereby forming thecomposition, wherein steps a)-c) can be performed in any order, andwherein step a) can be performed before, simultaneously, or after anyone of steps b)-f).
 87. The method of claim 86, wherein the methodfurther comprises distributing the composition into container andoverlaying the composition with an inert gas to exclude oxygen.